Wettstein et al. Stem Cell Research & Therapy 2014, 5:18http://stemcellres.com/content/5/1/18
RESEARCH Open Access
Progenitor cell therapy for sacral pressure sore:a pilot study with a novel human chronicwound modelReto Wettstein1*†, Miodrag Savic1†, Gerhard Pierer1, Oliver Scheufler1, Martin Haug1, Jörg Halter2, Alois Gratwohl2,Michael Baumberger3, Dirk Johannes Schaefer1 and Daniel Felix Kalbermatten1
Abstract
Introduction: Chronic wounds are a major health-care issue, but research is limited by the complexity and heterogeneityin terms of wound etiology as well as patient-related factors. A suitable animal model that replicates the situation inhumans is not available. Therefore, the aim of the present work is to present a standardized human wound modeland the data of a pilot study of topically applied progenitor cells in a sacral pressure sore.
Methods: Three patients underwent cell harvest from the iliac crest at the time of the initial debridement. Forty-eighthours after bone marrow harvest and debridement, the CD34+ selected cell suspension was injected into the wound.With the aid of a laser scanner, three-dimensional analyses of wound morphometry were performed until the defectwas reconstructed with a local flap 3 weeks after debridement.
Results: Decreases in volume to 60%± 6% of baseline on the sham side and to 52%± 3% of baseline on the cell sidewere measured. Histologic work-up revealed no signs of metaplastic, dysplastic, or neoplastic proliferation/differentiationafter progenitor cell treatment. CD34+ cells were detected in the biopsies of day 0.
Conclusions: The pressure sore wound model allows investigation of the initial 3 weeks after cell-based therapy.Objective outcome analysis in terms of wound volume and histology can be performed without, or with, minimaladditional morbidity, and the anatomy of the sacral area allows a control and study side in the same patient. Therefore,this model can serve as a standard for wound-healing studies.
IntroductionChronic wounds are an enormous burden for the patientsand their families, represent a major challenge for thetreating clinicians, and have a tremendous impact onhealth-care costs. A considerable amount of research hasbeen dedicated to different types of wound dressings. Theimpact of these modern dressing types on wound healing,however, is frequently disappointing as their efficacy hasnot been validated in late-stage clinical trials. This may berelated to the fact that single agents cannot interfere withthe complex interplay of wound healing.
* Correspondence: [email protected]†Equal contributors1Department of Plastic, Reconstructive, Aesthetic and Hand Surgery,University Hospital of Basel, Spitalstrasse 21, CH-4031 Basel, SwitzerlandFull list of author information is available at the end of the article
Recent interest in the treatment of chronic wounds hasshifted from the type of dressing—with or without pharma-ceutical agents and growth factors—to cell-based therapies.Stem cell therapies, using hematopoietic stem cells for non-hematopoietic indications as well as non-hematopoieticstem cells for tissue repairs, have increased over the lastyears for a broad series of indications [1]. Promising resultshave been reported in the treatment of small series of mainlychronic lower-extremity wounds with bone marrow-derivedstem cells [2-9]. The rationale behind the use of cell-basedtherapies—besides the presence of macro- and microvascu-lar disease leading to ischemia and hypoxia or hypergly-cemia, infection, and inflammatory reactions and so on—isthe fact that cells in chronic wounds are phenotypicallyaltered or senescent or both [10,11]. Therefore, they havea limited capacity to divide and are less responsive to
ral Ltd. This is an open access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.
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stimulation by growth factors. Also, the multimodal proper-ties of stem and progenitor cells that create a local environ-ment conductive to wound healing are lacking.One of the major problems in chronic wound research
is the heterogeneity of the patient population sufferingfrom chronic wounds in terms of ulcer etiology (that is,traumatic, diabetic, venous, arterial, mixed, pressure, andradiation-induced). In addition, ulcer size and localizationvary as patient comorbidities, overall health status, nutri-tional status, and social environment do. On the otherhand, the combination of different treatment modalities,the timing and mode of their application, and the pre- andpost-treatment wound care to obtain stable wound closurewithout recurrence—the ultimate goal—differ in manyways and render an objective analysis of any potentialbenefit of a treatment strategy difficult, not to mention thedifferent sources and preparations of cells used in cell-based therapies.Another major issue in chronic wound research, besides
the heterogeneity of wound etiology and patient-related fac-tors, is the lack of suitable animal models replicating chronicwounds. Mimicking the complexity of chronic wounds in ananimal is currently not possible. This further underscoresthe need for a standardized human wound model. To im-prove these methodological limitations, a novel humanchronic wound model is presented that allows a standard-ized, objective outcome analysis of the wound dimensions,for histological work-up and ideally for a direct comparisonof two different treatment modalities in the same patient. Inthis pilot study, the effect of topically applied hematopoietic-derived progenitor cells on wound healing in a sacral pres-sure sore wound model was evaluated.
Patients and methodsPatientsComplete para- or tetraplegic patients who were hos-pitalized at the Swiss Paraplegic Center in Nottwil,Switzerland, and who presented with a primary sacralpressure sore grade III-IV (that is, without bone involve-ment and signs of osteomyelitis) were prospectivelyincluded in the study. Exclusion criteria were age of lessthan 18 or more than 50 years and presence of HIV,hepatitis B or C, active malignancy, malnutrition, dia-betes mellitus, smoking, cardiopulmonary disease, per-ipheral arterial vascular disease, or systemic diseases likechronic polyarthritis, lupus, or scleroderma. Also, pa-tients on steroids, chemotherapeutics, or oral anticoagu-lants were excluded from the study. The protocol wasapproved by the local institutional review board of theCanton of Lucerne (#552). Written informed consentwas obtained from all patients included in the study andincluded approval for publication of information aboutthemselves and fotodocumentation in this journal. Eachpatient signed these forms of consent.
Wound preparationWound debridement was performed in a standardizeden-bloc technique in the operation room under sterileconditions. Hemostasis was achieved by cauterization andapplication of warm compresses. For all operations, min-imal anesthesia care was provided for patient monitoring.No local or systemic anesthetics were necessary in this pa-tient group. Wound dressings during the entire studyperiod were performed with moist gauzes (Ringer’s lactate)twice a day. No disinfectant substances were used.
Cell harvest and progenitor cell isolationAt the time of wound debridement, bone marrow (100 mL)was harvested from the posterior iliac crest by repetitivepunctures and aspirations. Cell count, CD34 count, viabil-ity, and microbiologic cultures were performed at the stemcell laboratory of the University Hospital of Basel. Afterovernight storage, CD34 selection was performed withmagnetic beat-loaded antibodies with the CliniMACS cellseparation model CS2-CE/UL (Miltenyi Biotec, BergischGladbach, Germany). After selection, cell count, CD34 andlymphocyte subclass counts, viability and sterility tests wereperformed. Cells were once again stored overnight and thenconcentrated.
Progenitor cell therapyForty-eight hours after bone marrow harvest and de-bridement, the CD34+ selected stem cell suspension wasinjected into the wound. One side of the wound wastreated by injection of the cell suspension, and the otherside served as control and was treated with an identicalvolume of NaCl 0.9%. For injection, the wound was sub-divided with a grid into small areas of 1 cm2 (Figure 1).Fractionated injections were performed into the woundbed as well as perifascially, subcutaneously, and subder-mally at the borders of the wound.
EndpointsWound morphometryChanges in wound diameter and defect volume wereassessed with a three-dimensional (3D) laser scanner (VI-910 Non-contact 3D digitizer; Konica Minolta Inc., Tokyo,Japan). The method has been described in detail elsewhere[12,13]. Briefly, with the patient in the prone position, thescanner was positioned parallel to the wound with acustom-made carrier that essentially consists of a C-shapedframe that permits the scanner to be positioned over thebed, at a fixed distance from the pressure sore. The cap-tured images were imported with the Geomagic studio 12program (Geomagic Inc., Raleigh, NC, USA) and convertedinto a single virtual 3D model for further analysis. Care wastaken that the patient was lying flat without any sheets orpillows that may create an oblique incidence. With Free-Form modeling plus and Phantom desktop software
Figure 1 Mapping of the pressure sore 48 hours after debridement with the planned injections sites for the stem cells on the left side.(a) The stem cell solution is used on one side of the pressure sore, and a sham solution is used on the other side (at a distance of 1 cm in radiusaround injection sites). The midline can easily be identified by orientation of anatomical landmarks (rima ani, spine, or the anus). For the sake ofclarity, the injection points on the control side are not included in the picture. (b) Injection of the progenitor cells.
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(Sensable, Wilmington, MA, USA), the borders of the pres-sure sore are marked. In this procedure, in contrast to otherplastic surgical procedures in which laser scanning can beused (for example, breast volume changes), definition of theborders is unequivocal in sacral pressure sores. Also, themidline of the pressure sore can be easily defined by orien-tation on the spine cranially and the rima ani caudally.Since there is no undermining of the wound edges after thedebridement, no shadows occur. Two patches representingthe two sides of the defect were created. The surface of thepatches was adapted to the anatomic curvature of thesacrum. The respective dimensions of the treated and un-treated sides can then be calculated and were indicated inabsolute values.
HistologyFor histological examination, two punch biopsies of 2 mmin diameter were harvested at two sites on each side of thewound on corresponding localizations at days 0 (day ofstem cell injection), 3, 5, 12, and 19 (that is, at the differentphases of wound healing). To avoid taking biopsies fromthe same location twice, a clockwise rotation was per-formed in predefined sectors. Biopsies were fixed in 4%buffered formaldehyde and paraffin-embedded. The slides(10 μm) were stained with hematoxylin-eosin, Giemsa,and periodic acid-Schiff staining for analysis of signs ofmetaplasia, dysplasia, or malignant transformation. Foridentification of CD34+ cells, an immunohistochemical re-action with intrahepatic leukocyte-4 (IHL-4) was per-formed. No anesthesia was required for harvesting thebiopsies.
Study protocolIn keeping with the general treatment concept of pres-sure sores at our institution, all wounds were debrided,conditioned, and reconstructed after 21 days [14]. At theinitial debridement session, cells were harvested fromthe posterior iliac crest. Forty-eight hours later, the cellswere injected into the wound. In all patients, the left side
of the pressure sore was treated with cells. Biopsies weretaken at the initial debridement and on days 0 (day ofstem cell application), 3, 5, 12, and 19 after cell applica-tion. For scanning analysis, day 5 was considered thebaseline value in order to eliminate any potential con-founding factors such as edema by surgical trauma andlocal fluid irrigation. Flap coverage of the defect was per-formed after re-debridement and the last endpointassessment. Clinical follow-up of 2 years after cell appli-cation was chosen for clinical monitoring for any signsof development of malignancy.
ResultsPatientsOf a total of 35 patients presenting with sacral pressuresores between January 2007 and December 2008, threemale patients met the restrictive inclusion criteria. Theages of the patients were 40, 20, and 49 years. Exclusioncriteria were pressure sores of higher than grade IV in11 cases, comorbidities in 10 cases, and absence of in-formed consent in three cases, and three patients hadpreserved sacral sensibility. Three patients were tooyoung, two patients presented with osteomyelitis, andone had positive bacterial culture of the bone marrowaspirate. The study was finished prematurely to widenthe inclusion criteria.
Cell injectionThe total numbers of injected CD34+ cells were 25.5 ×106 (patient 1: 4.2 mL), 18.3 × 106 (patient 2: 4.5 mL),and 17.4 × 106 (patient 3: 3.8 mL). The values of injectedCD34+ cell count/cm2 of the treated wounds were 0.5 ×106, 2.2 × 106, and 0.6 × 106 cells/cm2 for patients 1, 2,and 3, respectively.
HistologyIn total, 120 biopsies were examined at the Institute ofPathology, University Hospital Basel, Switzerland. Noneof the biopsies showed signs of metaplastic, dysplastic,
Table 1 Wound morphology data
Volume, cm3 Circumference, mm
Control side Stem cell side Control side Stem cell side
Patient 1 905 660 190 180
Patient 2 53 36 77 70
Patient 3 253 310 138 138
Absolute values as assessed by three-dimensional laser scanning at day 5 ofthe volume of the pressure sore and the circumference.
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or neoplastic proliferation/differentiation after progeni-tor cell treatment. CD34+ stem cells were detected inthe biopsies of day 0 (day of application) (Figure 2).From day 3 on, progenitor cell could not be identifiedwith certainty anymore.
Three-dimensional laser scansThe total volume and circumference of the treated anduntreated sides of the pressure sores at day 5 are sum-marized in absolute values in Table 1. Within the 14days from day 5 to day 19, there were decreases in vol-ume to 60% ± 6% of baseline on the sham side and to52% ± 3% of baseline on the progenitor cell side(Figure 3). Changes in the circumference of the twosides were less spectacular, with decreases to 86% ± 9%and 82% ± 4% of baseline on the sham and progenitorcell sides (Figure 4).
Follow-upHealing after flap surgery was uneventful in the threepatients. During the regular follow-up examinations for2 years post-operatively, no signs of malignancy were de-tected by local clinical inspection and palpation.
DiscussionBasically, standard treatment for advanced pressuresores in plegic patients consists of debridement, woundconditioning, and pressure offload followed by defectclosure with local flap procedures [14]. The time forwound bed preparation between debridement and defectclosure is usually about 3 weeks. This interval representsa window for experimental investigations. Since most ofsacral pressure sores cross the midline—a landmarkwhich is easily identified and which can serve as anorientation in the analysis of scanning—each patient,
Figure 2 Biopsy at day one confirming the presence of CD34+
progenitor cells marked in brown (immunohistochemicalreaction with intrahepatic leukocyte-4 (IHL-4). Magnification 20×.
respectively one of the two halves of the pressure sorecan serve as control. The midline represents an easilyidentifiable landmark that permits to consistently dividethe sacral pressure sore in a left and right half, respect-ively a control and treatment side. Another advantage ofthe flat wound appearance is the accessibility for scans.In flat wounds, compared with deep wounds, there arefewer scan shadows, thus reducing the number of scansneeded to get the whole picture. In addition, it is routinepractice to excise the wound borders and ground beforeflap closure, a manoeuver that provides local controlafter application of test agents. During scanning and bi-opsies, the patient remains in a comfortable prone pos-ition, and this increases the patient’s compliance greatly,reducing the biopsy process time and increasing thequality of the scans by reducing body movement. An-other advantage of this wound model is that intermedi-ate biopsies can be harvested without significantadditional morbidity and without the need for anesthesia(in complete para-/tetraplegic patients), which may posi-tively influence the quality of the histologic work-up.In the three patients included in this pilot study, the sin-
gle application of autologous, isolated, but unexpandedhematopoietic stem cells seems to positively influencegranulation tissue formation and wound contraction asassessed by 3D laser scanning, which showed about a 50%reduction in the volume of the pressure sore on thetreated side versus a 40% reduction on the control side.
Figure 3 Decrease in the volume of the wound on the control side(dotted line) and the stem cell side (continuous line) normalized tothe values of day 5 (mean± standard deviation). D, day.
Figure 4 Laser scanning images of the same pressure sore. Image-processed scans of a treated pressure sore (a) after treatment and at(b) 5 days, (c) 12 days, and (d) 19 days.
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Obviously, the number of patients is very small and the re-sults cannot be analyzed statistically and the biological orclinical benefit may be minimal at best; however, the aimsof study were to establish this pressure sore model and toexclude any signs of malignancy after local application ofcells in these three patients who were observed for 3weeks. The number of patients and the follow-up certainlyrender any comment on safety and efficacy of this ap-proach impossible. The strict inclusion criteria in thissafety study restricted the number of patients includedconsiderably. A reduction in ulcer size of more than 70%when compared with 30% in control subjects was identi-fied after 12 weeks; however, cells were administered sev-eral times [8]. The interval for maximal action of a cell-based therapy in a previous study has shown that nochanges occurred after 14 days, a time point at which min-imal wound size was measured after a single cell applica-tion [15]. Fibroblasts, which are attracted from the edge ofthe wound or from the bone marrow, are stimulated bymacrophages and some differentiate into myofibroblasts[16]. This effect might be accentuated by applying stemcells into the wound and may partly explain the trend to-ward increased wound contraction observed in the presentstudy. In the present study, the amount of wound volumereduction by the formation of granulation tissue is lessrelevant since defect closure was performed with a flap.For most clinical cases, stimulation of granulation tissueformation, increased wound contracture and epithelialisa-tion would be the primary goals in order to shorten theoverall treatment period.Different reports on cell-based chronic wound therapy
showed a positive influence on wound healing; however,a precise and objective analysis of the effect of the ther-apies used is difficult, and frequently there are no dataon wound contracture, development of granulation tis-sue, or epithelialization [3,5,7,8,15,17-19]. Some of thesereports show complete healing of long-lasting chronic,usually lower extremity, wounds. However, either mul-tiple cell applications or combinations of cell therapyand skin grafting procedures were used and led eventu-ally to wound closure. Whereas stable wound closure isthe clinically important endpoint, the pathophysiologicalmechanisms underlying the conversion from a chronic
wound, with its derangements in the healing cascade, toa healing wound need further investigation. The sacralpressure sore model is ideal to analyze the initial periodof wound changes after cell application (that is, the con-version from a non-healing to a healing wound); how-ever, it has the obvious disadvantage that healing bysecondary intention would take a long time, potentiallyyield unstable scar tissue at the site of pressure, andtherefore be unethical. In this pilot study, no attemptwas made to establish a dose dependency of the cell-based therapy, and the patients received differentnumbers of cells in total and per surface area treated.Obviously, in a large-scale study, the number of cellsadministered should be matched to the defect size.In terms of safety, histological analysis did not reveal
any signs of malignant transformation in the presentstudy. This has been corroborated by different studiesusing bone marrow-derived cells for the treatment ofchronic wounds, where no changes in inflammatory re-actions or in differential blood count were observed orchanges in laboratory analysis occurred [8,15]. The long-term clinical follow-up examinations did not show anysigns of cancerous masses in the area of treatment. Also,adverse effects of the cell application have not been ob-served in the present study or previously reported. Al-though malignant transformation is an uncommon eventin the chronic wound environment [20], studies showedthat signaling pathways of healing skin wounds stronglyresemble those of malignant tumors [21]. Our resultsshowed that there is no sign of malignant transformationduring the observed period. Furthermore, the design ofthe study reduces the potential risk of progenitor-cell in-duced malignant tissue transformation by the fact thatthe treated area is totally excised before surgical woundclosure.Future studies with this model will allow researchers to
analyze the effect of cell preparation, selection, culture,and storage and to identify the potential of cells fromother sources than bone marrow, which is a very well-known origin of hematopoietic and non-hematopoieticstem cells, including mesenchymal stem cells. Obviously,proper characterization of cells is essential in order to ob-tain consistent, reproducible results. Another essential
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parameter is the concentration of cells, since a relationshipbetween the number of cells applied and the decrease inwound size observed has been reported [2]. Since the earlyinflammatory phase is characterized by migration into thewound of monocytes, which differentiate into macro-phages [22] and since bone marrow-derived cells from thehematopoietic stem cell lineage increase in number in der-mal wounds and lead to increased wound contraction[23], hematopoietic stem cells were used in this pilotstudy. Also, the harvesting of bone marrow at the time ofthe initial debridement did not require patient reposi-tioning and was easy to perform. With increasing know-ledge about stem cells, it seems as if different sources ofcells may be used and may result in similar effects.One of the issues in stem cell-based wound therapy is
the mode of cell delivery [24]. In the present model, thecells were injected directly into the wound borders andwound ground, which was possible since pressure soreswith exposed bone were not included in the study. Directinjection in the wound ground can be difficult in long-standing leg ulcers with a thick layer of dense scar tissue,which is sometimes accompanied by calcifications. Poten-tial alternatives to direct injection are cell suspension in fi-brin glue [2] and impregnation in a collagen matrix [6].Obviously, the wound ground has to provide a criticalvascularization for the cells to survive. One of the reasonsto perform surgical debridement is to remove fibrin, nec-rotic tissue, and scar tissue to obtain a bleeding woundbed. This, however, is probably the major problem inchronic leg ulcers, in which a through debridement fre-quently exposes tendons or bone or a limited debridementonly leads to scarce bleeding points. In such a situation,the injection of the cells is supposed to induce neoangio-genesis, which ultimately leads to the formation of granu-lation tissue. Cell-enhanced dressings are probably of littlevalue in such situations. Another limitation of this study isthat the patient served as his own control, and it cannotbe excluded that homing of the cells applied to the saline-treated control occurred and had a positive influence onthis side as well.
ConclusionsThe proper and safe use of progenitor cells, as well asthe ideal source and type of cells, is currently notknown. One of the reasons is the lack of a suitablemodel to investigate the effects of cell-based therapieson chronic wounds. The presented pressure sore woundmodel allowed us to investigate the initial 3 weeks aftercell-based therapy and thereby to further elucidate theunderlying pathophysiologic mechanisms. Since object-ive outcome analysis in terms of wound volume andhistology can be performed with no or minimal add-itional morbidity, this model can serve as a standardmodel for wound healing. In this pilot feasibility and
safety study, there was a trend toward increased granula-tion tissue formation and wound contracture in thethree patients assessed.
Competing interestsThe authors declare that they have no competing interests.
Authors’ contributionsMS carried out patient management, stem cell treatment, assessment ofresults, and histologic work-up and helped to write the manuscript. RWand DJS carried out study design and data analysis, helped to write themanuscript, but received no funding. GP and MH carried out study design,helped to revise the manuscript, but received no funding. OS carried outstudy design, patient management, and stem cell treatment but received nofunding. JH and AG carried out study design and stem cell preparation,helped to revise the manuscript, but received no funding. MB carried outstudy design and patient management, helped to revise the manuscript, butreceived no funding. DFK carried out study design, patient management,and data analysis, helped to write the manuscript, but received no funding.All authors read and approved the final manuscript.
AcknowledgmentsInformed written consent was obtained from the patients for publication ofthis article and accompanying images. The Swiss Paraplegic Foundationsupported the study in terms of logistics and materials and was not involvedin design, collection, analysis, or interpretation or the decision to publish thearticle. None of the authors received any funding from the Swiss ParaplegicFoundation for this work.
Author details1Department of Plastic, Reconstructive, Aesthetic and Hand Surgery,University Hospital of Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland.2Clinic of Hematology, University Hospital of Basel, Petersgraben 4, CH-4031Basel, Switzerland. 3Swiss Paraplegic Center Nottwil, Guido A. Zäch-Strasse 1,CH-6207 Nottwil, Switzerland.
Received: 11 February 2013 Revised: 8 September 2013Accepted: 14 January 2014 Published: 29 January 2014
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doi:10.1186/scrt407Cite this article as: Wettstein et al.: Progenitor cell therapy for sacralpressure sore: a pilot study with a novel human chronic wound model.Stem Cell Research & Therapy 2014 5:18.
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